Pyridylaminoalkylamine intermediates

ABSTRACT

Pyridine derivatives are disclosed which are useful as histamine H 1  -antagonists.

This is a division of application Ser. No. 563,497 filed Dec. 20, 1983,now U.S. Pat. No. 4,548,940, issued Oct. 22, 1985.

This invention relates to certain pyrimidone derivatives, a process fortheir preparation, compositions containing them and their use ashistamine H₁ -antagonists.

Histamine, a physiologically active compound endogenous in mammals,exerts its action by interacting with certain sites called receptors.One type of receptor is known as a histamine H₁ -receptor (Ash andSchild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histamine atthese receptors are inhibited by drugs commonly called "antihistamines"(histamine H₁ -antagonists) a common example of which is mepyramine.

A class of pyrimidone derivatives has now been discovered the members ofwhich have histamine H₁ -antagonist activity and are useful for thetreatment of diseases (for example bronchial asthma, rhinitis, hayfeverand allergic eczema) whose symptoms are mediated through the action ofhistamine at H₁ -receptors.

Accordingly, the present invention provides compounds of formula (1):##STR1## and pharmaceutically acceptable acid addition salts thererofwhere R¹ is 2- or 3-pyridyl optionally bearing one or two substituentswhich are the same or different and which are C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, nitro, cyano or trifluoromethyl;

a is 2 to 4; and

R² is phenyl optionally bearing one or two substituents which are thesame or different and are halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy ora methylenedioxy group or is 3-pyridyl; N-oxo-3-pyridyl;6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl; 6-hydroxymethyl-3-pyridyl;4,6-dimethyl-3-pyridyl; N-oxo-4,6-dimethyl-3-pyridyl;6-hydroxymethyl-4-methyl-3-pyridyl; 5,6-dimethyl-3-pyridyl;N-oxo-5,6-dimethyl-3-pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl;4-pyridyl or N-oxo-4-pyridyl.

Examples of C₁₋₄ alkyl substituents for R¹ are methyl, ethyl andn-propyl.

Examples of C₁₋₄ alkoxy substituents for R¹ are methoxy, ethoxy andn-propoxy.

Examples of halogen substituents for R¹ are fluoro, chloro and bromo.

Preferably R¹ is an optionally substituted 2-pyridyl group.

Preferably the 2-pyridyl group R¹ has two substituents one of which isin the 3-position and one of which is in the 5-position.

Preferably the substituent in the 5-position is halogen and inparticular it is chlorine.

Preferably the substituent in the 3-position is halogen or C₁₋₄ alkyl.More preferably it is C₁₋₄ alkyl and in particular it is methyl.

The value for a can be 2, 3, or 4. Thus --(CH₂)_(a) -- can beethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl. Preferably a is 3so that --(CH₂)_(a) -- is propane-1,3-diyl. When R² is optionallysubstituted phenyl, preferably the phenyl group is substituted in themeta and/or para position relative to its point of attachment to the CH₂group. Thus particular groups which R² represents are 3-methoxyphenyl,4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl,4-methoxyphenyl or 5-(3,4-methylenedioxyphenyl).

Preferably R² is 6-methyl-3-pyridyl.

The compounds of formula (1) are shown and described as 4-pyrimidoneswhich exist in equilibrium with the corresponding 6-one tautomers. Thesecompounds also exist to a lesser extent as the hydroxy tautomers, andthe pyrimidine ring may also exist in the following tautomeric forms:##STR2##

It will be understood that all these tautomeric forms are within thescope of the present invention.

The compounds of formula (1) form pharmaceutically acceptable salts withpharmaceutically acceptable salt-forming acids. Examples of these acidsare hydrochloric, sulphuric, hydrobromic, phosphoric, tartaric, citric,maleic, lactic, 2-hydroxyethanesulphonic, methanesulphonic,toluene-4-sulphonic, ethanedisulphonic, ethanesulphonic andcamphorsulphonic acids.

Compounds of formula (1) can be prepared by reacting a compound offormula (2):

    R.sup.1 X.sup.1                                            ( 2)

where R¹ is as defined with reference to formula (1) and X¹ is halogenor a group --NH(CH₂)_(a) NH₂ where a is as defined with reference toformula (1) with a compound of formula (3): ##STR3## where R³ is phenyloptionally bearing one or two substituents which are the same ordifferent and are halogen, optionally protected hydroxy, C₁₋₄ alkyl orC₁₋₄ alkoxy or a methylenedioxy group or is 3-pyridyl; N-oxo-3-pyridyl;6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl; 4,6-dimethyl-3-pyridyl;N-oxo-4,6-dimethyl-3-pyridyl; methyl-4-methyl-3-pyridyl;5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-pyridyl; 4-pyridyl orN-oxo-4-pyridyl;

X² is a group NH₂ (CH₂)_(a) NH-- where a is as defined with reference toformula (1) when X¹ is halogen, or is a group displaceable by amino whenX¹ is a group --NH(CH₂)_(a) NH₂, thereafter removing any hydroxyprotecting groups, optionally converting the compound of formula (1) soobtained where R² is N-oxo-6-methyl-3-pyridyl;N-oxo-4,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-pyridyl; into thecorresponding compound of formula (1) where R² is6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-pyridyl; or6-hydroxymethyl-5-methyl-3-pyridyl; and thereafter optionally convertinga compound of formula (1) so obtained into a salt.

The reaction can be carried out at an elevated temperature in theabsence of a solvent, for example at from 80° C. to 170° C., preferablyfrom 120° C. to 140° C., or in a solvent at an elevated temperature, forexample at the reflux temperature of the reaction mixture. The choice ofsolvent is affected by solubility characteristics of the reactants.Preferably the solvent is pyridine, a picoline or mixture of picolines,a C₁₋₄ alkanol, preferably ethanol or 1-propanol, 1,2-ethanediol, a highboiling alkoxyaryl ether for example anisole, or a polar aproticsolvent, for example dimethylformamide, dimethylacetamide,dimethylsulphoxide, hexamethylphosphoramide, or sulpholane,

Examples of groups X² are C₁₋₄ alkylthio (particularly methylthio),benzylthio, chlorine, bromine and nitroamino. Preferably X² isnitroamino.

The compounds of formula (1) where R² is N-oxo-6-methyl-3-pyridyl;N-oxo-4,6-dimethyl-3-pyridyl; or N-oxo-5,6-dimethyl-3-pyridyl can beconverted into the corresponding compound of formula (1) where R² is6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-pyridyl; or6-hydroxymethyl-5-methyl-3-pyridyl; by reacting with an organicanhydride for example trifluoroacetic anhydride.

Examples of hydroxy protecting groups are methoxymethyl,methylthiomethyl, tetrahydropyranyl, arylmethyl, for example benzyl,C₁₋₆ alkyl, for example methyl, and alkanoyl, for example formyl oracetyl.

These protecting groups can be removed by standard methods, for examplewhere the protecting group is alkanoyl or C₁₋₆ alkyl, by acidhydrolysis.

Pharmaceutically acceptable salts of compounds of formula (1) can beprepared by standard methods, for example by reacting a solution of thecompound of formula (1) with a solution of the acid.

Compounds of formula (2) where X¹ is --NH(CH₂)_(a) NH₂ can be preparedby reacting a compound of formula (2) where X¹ is halogen with a diamineof formula (4):

    NH.sub.2 (CH.sub.2).sub.a NH.sub.2                         ( 4)

where a is as defined in formula (1).

Compounds of formula (3) where X² is NH₂ (CH₂)_(a) NH-- can be preparedby reacting a compound of formula (3) where X² is a group displaceablewith amine with a diamine of formula (4) as defined above.

These reactions, that is for the preparation of compounds of formula (2)where X¹ is --NH(CH₂)_(a) NH₂ and compounds of formula (3) where X² isNH₂ (CH₂)_(a) NH--, can be carried out under conditions described abovefor the preparation of compounds of formula (1) that is at an elevatedtemperature in the absence of a solvent, for example at from 80° C. to170° C., preferably from 120° C. to 140° C., or in a solvent at anelevated temperature, for example at the reflux temperature of thereaction mixture. The choice of solvent is affected by solubilitycharacteristics of the reactants. Preferably the solvent is pyridine, apicoline or mixture of picolines, a C₁₋₄ alkanol, preferably ethanol or1-propanol, 1,2-ethanediol, a high boiling alkoxyaryl ether for exampleanisole, or a polar aprotic solvent, for example dimethylformamide,dimethylacetamide, dimethylsulphoxide, hexamethylphosphoramide, orsulpholane.

Compounds of formula (2) where X¹ is halogen and compounds of formula(4) are known or can be made by analogy with known methods. Compounds offormula (3) where X² is a group displacable with amino are known or canbe made by analogy with known methods as described in U.S. Pat. No.4,145,546 and European Patent Application No. 0068833.

The histamine H₁ -antagonist activity of the compounds of formula (1)can be demonstrated in vitro in the guinea pig ileum test. In this testan isolated portion of the guinea pig ileum is secured under tension(500 mg) between an anchorage and a transducer in a 10 ml tissue bathand immersed in magnesium free Tyrode solution with constant aeration ata temperature of 30° C. The output from the transducer is amplified. Theamplified output is in turn fed to a flat bed recorder. Measured amountsof histamine are added to the tissue bath so that the histamineconcentration increases step-wise until the force of the contractionreaches a maximum. The tissue bath is washed out and filled with freshmagnesium free Tyrode solution containing compound under test. Thesolution is left in contact with the tissue for 8 min. and measuredamounts of histamine are added again until a maximum contraction isrecorded. The assay is repeated with increasing concentrations of testcompound and the dose of histamine giving 50% of maximum contraction isnoted. A dose ratio (DR) was calculated by comparing the concentrationsof histamine required to produce 50% maximum response in the absence andin the presence of the antagonist. A plot of Log DR-1 against Log D (theconcentration of compound under test) is made and the point ofintersection with the Log (DR-1) ordinate is taken as the measure of theactivity (pA₂ value). The compounds of Examples 1 to 28 have pA₂ valuesgreater than 6.

The activity of compounds of formula (1) as histamine H₁ -antagonistscan be demonstrated in vivo by the inhibition of histamine inducedbronchoconstriction. Guinea pigs of either sex are anaesthetised byintraperitoneal injection of sodium pentobarbitone, 90 mg/kg. Thetrachea is cannulated. The animal is respired artificially with a fixedvolume of air just adequate to inflate the lungs. The pressure needed toinflate the lungs is monitored from the respiratory system using a lowpressure transducer. Intravenous injection of histamine causesdose-dependent increases in the pressure to inflate the lungs reflectingthe bronchoconstrictor action of histamine. Responses to histamine canbe antagonised using histamine H₁ -receptor antagonists.

Dose-response curves to histamine are established at 20, 40, 80, 160 and320 nmols/kg. Antagonists are then administered by intravenous injectionand 5 minutes later a new histamine dose-response curve is establishedincreasing the doses of histamine as necessary. The effect of theantagonist can be quantified by the displacement, to the right, of thehistamine dose-response curve, expressed as a dose-ratio. A series ofdoses of antagonists may be given to each animal allowing calculation ofdose-ratios for each dose of antagonist. The compounds of the Exampleshereafter cause displacement of histamine dose-response curves with adose-ratio of 10 at doses of less than 100 micromole kg⁻¹ i.v.

In order to use the compounds of the invention as histamine H₁-antagonists, they can be formulated as pharmaceutical compositions inaccordance with standard pharmaceutical procedure.

The invention also includes pharmaceutical compositions comprising acompound of formula (1) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

Compounds of formula (1) and their pharmaceutically acceptable salts canbe administered topically or systemically.

Topical formulations for administration to the skin include lotions andcreams. Topical formulations for administration to the respiratory tractinclude solutions for application via a nebulizer or as an aerosol, or amicrofine insufflatable powder. The active ingredient in aninsufflatable powder has a small particle size i.e. less than 50 micronsand preferably less than 10 microns. The active material is co-presentedwith a solid carrier for example lactose which has a particle size ofless than 50 microns.

Systemic administration can be achieved by rectal, oral or parenteraladministration. A typical suppository formulation comprises the activecompound with a binding agent and/or lubricating agent for examplegelatine or cocoa butter or other low melting vegetable waxes or fats.Typical parenteral compositions consist of a solution or suspension ofthe active material in a sterile aqueous carrier of parenterallyacceptable oil.

Compounds of formula (1) which are active when given orally can beformulated as syrups, tablets, capsules and lozenges. A syrupformulation generally consists of a suspension or solution of thecompound in a liquid carrier for example ethanol, glycerine or waterwith a flavouring or colouring agent. Where the composition is in theform of a capsule, the solid in granular form optionally with a bindingagent is encased in a gelatin shell. Where the composition is in theform of a tablet, any suitable pharmaceutical carrier routinely used forpreparing solid formulations can be used. Examples of such carriersinclude magnesium stearate, starch, lactose, glucose, sucrose, andcellulose. Preferably the composition is in unit dose form for example atablet, capsule or metered aerosol.

Where appropriate, bronchodilators and anti-asthmatics for examplesympathomimetic amines particularly isoprenaline, isoetharine,salbutamol, phenylephrine and ephedrine; xanthine derivativesparticularly theophylline and aminophylline; and corticosteroidsparticularly prednisolone and adrenal stimulants particularly ACTH canbe included.

Each dosage unit for oral administration contains preferably from 1 to200 mg of a compound of formula (1) or a pharmaceutically acceptablesalt thereof calculated as the free base.

The invention also provides a method of blocking histamine H₁ -receptorswhich comprises administering to a subject an effective amount to blocksaid receptors of a compound of formula (1) or a pharmaceuticallyacceptable salt thereof.

The compounds of formula (1) and their pharmaceutically acceptable saltswill normally be administered to a subject in a pharmaceuticalcomposition as described above, for the treatment of rhinitis, hayfever,bronchial asthma or allergic eczema. An adult subject will receive anoral dose of between 15 mg and 400 mg and preferably between 15 mg and200 mg or an intravenous, subcutaneous or intramuscular dose of between1 mg and 50 mg, and preferably between 1 mg and 10 mg of a compound offormula (1) or a pharmaceutically acceptable salt thereof calculated asthe free base, the composition being administered 1 to 4 times per day.

The following Examples illustrate the invention.

EXAMPLE 1

(i) 2-Bromopyridine (20 g), 1,3-diaminopropane (47 g) and pyridine (13ml) were heated together under reflux for 2.5 hr. The mixture wasstripped to remove the excess of diaminopropane and the residue taken upin water. The pH was adjusted to 14 and extracted with chloroform. Theextracts were dried (K₂ CO₃), stripped and the residue distilled atreduced pressure to give 2-(3-aminopropylamino)pyridine (13.3 g; 70%)b.p.₀.02 90°-91° C.

(ii) 2-(3-Aminopropylamino)pyridine (1.74 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (2.0 g) wereheated together under reflux in pyridine (8 ml) for 22 hr. The mixturewas stripped, the residue triturated with ether and then water (the pHof which was adjusted to 6.5 with dilute acetic acid) to give a whitesolid. Recrystallisation from isopropanol gave2-[3-(pyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone,(1.87 g; 70%), m.p. 163°-165° C.

C₁₉ H₂₂ N₆ O+1.6% w/w isopropanol: Found: C, 64.84; H, 6.51; N, 23.41;requires: C, 65.04; H, 6.44; N, 23.60%.

EXAMPLE 2

(i) 2-Bromo-5-methylpyridine (17.2 g), 1,3-diaminopropane (37 g) andpyridine (10 ml) were heated together under reflux for 6 hr. The mixturewas stripped to remove excess diaminopropane and the residue taken up inwater. The pH was adjusted to 7.5 with conc. hydrochloric acid andextracted with chloroform. The aqueous solution was basified with conc.sodium hydroxide to pH 14 and extracted again with chloroform. Theextracts were dried (K₂ CO₃) and stripped to give2-(3-aminopropylamino)-5-methylpyridine as an oil (9.95 g; 60%) whichwas used without further purification.

(ii) Substituting 2-(3-aminopropylamino)-5-methylpyridine (1.9 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(5-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone2.2 H₂ O, (1.54 g; 50%) m.p. 164°-166° C. on recrystallisation fromisopropanol/water.

C₂₀ H₂₄ N₆ O.2.2H₂ O: Found: C, 59.49; H, 6.72; N, 20.84; requires: C,59.45; H, 7.08; N, 20.80%.

EXAMPLE 3

(i) Substituting 2,5-dichloropyridino (5.00 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave2-(3-aminopropylamino)-5-chloropyridine as an oil (1.36 g) which wasused without further purification.

(ii) Substituting 2-(3-aminopropylamino)-5-chloropyridine (1.3 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(5-chloropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidon1.9 H₂ O, (1.42 g; 58%) m.p. 173°-175° C. on recrystallisation fromisopropanol/water.

C₁₉ H₂₁ ClN₆ O.1.9H₂ O: Found: C, 54.58; H, 5.70; N, 19.96; Cl, 8.66;requires: C, 54.45; H, 5.96; N, 20.05; Cl, 8.46%.

EXAMPLE 4

(i) Substituting 2,5-dibromopyridine (10 g) for 2-bromo-5-methylpyridineand using the corresponding molar proportions of the other reagents inthe method of Example 2(i) gave 2-(3-aminopropylamino)-5-bromopyridineas an oil (9.1 g) which was used without further purification.

(ii) Substituting 2-(3-aminopropylamino)-5-bromopyridine (0.69 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave,after chromatography (silica gel, 5% ammoniacalmethanol/dichloromethane),2-[3-(5-bromopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonemonohydrate, (0.31 g; 28%) m.p. 186°-187° C. on recrystallisation fromisopropanol/water.

C₁₉ H₂₁ BrN₆ O.1H₂ O: Found: C, 51.22; H, 5.13; N, 18.72; Br, 17.59;requires: C, 51.01; H, 5.18; N, 18.79; Br, 17.86%.

EXAMPLE 5

(i) 2-Chloro-5-trichloromethylpyridine (5.0 g) and antimony trifluoride(3.88 g) were heated together on an oil bath at 170° C. to form ahomogeneous oil. Heating was continued under reflux for a further 5minutes after which time the condenser was directed downwards and thedistillate (b.p. 135°-140° C.) collected. The distillate was taken up indichloromethane and washed successively with 10% hydrochloric acid andwater. After drying (MgSO₄), the solution was stripped to give an oil(1.84 g) which was found to be a mixture of2-chloro-5-trifluoromethylpyridine and2-fluoro-5-trifluoromethylpyridine by GLC/mass spec (ratio ca. 3:1).

(ii) The mixture from the method of Example 5(i) (1.8 g) in pyridine(1ml) was added dropwise to 1,3-diaminopropane (4.1 ml) with stirring atroom temperature. After 24 hr. the mixture was stripped, the residuetaken up in water and the pH adjusted to 6.0 with hydrochloric acid. Thesolution was extracted with chloroform and the pH adjusted to 12.5 withsodium hydroxide. Extraction with ether gave, after drying (K₂ CO₃) andstripping, 2-(3-aminopropylamino)-5-trifluoromethylpyridine as an oil(0.86 g) which was used without further purification.

(iii) Substituting 2-(3-aminopropylamino)-5-trifluoromethyl pyridine(0.80 g) for 2-(3-aminopropylamino)pyridine and using the correspondingmolar proportions of the other reagents in the method of Example 1(ii)gave2-[3-(5-trifluoromethylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonedihydrate, (0.96 g; 75%) m.p. 220°-223° C. on recrystallisation fromisopropanol/water.

C₂₀ H₂₁ F₃ N₆ O.2H₂ O: Found: C, 52.52; H, 5.08; N, 18.22; requires: C,52.82; H, 5.55; N, 18.48%.

EXAMPLE 6

(i) 1,3-Diaminopropane (60 ml) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (5.22 g) wereheated together under reflux for 2.5 hr. Excess amine was stripped offand the residue recrystallised from ethanol to give2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (4.3g; 79%) m.p. 162°-164° C.

(ii) 2-Chloro-5-cyanopyridine (0.61 g),2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.09)and potassium carbonate (0.61 g) were heated together under reflux inpyridine (10 ml) for 2.5 hr. The mixture was stripped, the residue takenup in water and the pH adjusted to 3 with hydrochloric acid. Afterextracting with chloroform the aqueous solution was filtered and the pHraised to 6.5 with sodium hydroxide. The precipitate thus obtained waschromatographed (silica gel, chloroform/methanol, graded 1:0 to 20:1)and the required component recrystallised twice from ethanol to give2-[3-(5-cyanopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone0.2 H₂ O, (0.38 g; 25%) m.p. 175°-177° C.

C₂₀ H₂₁ N₇ O.O.2H₂ O: Found: C, 63.40; H, 5.79; N, 25.95; requires: C,63.37; H, 5.69; N, 25.87%.

EXAMPLE 7

(i) Substituting 2-bromo-3-methylpyridine (10 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave2-(3-aminopropylamino)-3-methylpyridine (6.93 g) as an oil which wasused without further purification.

(ii) Substituting 2-(3-aminopropylamino)-3-methylpyridine (2 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(3-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone1.75 H₂ O, (2.67 g; 68%) m.p. 119°-123° C. on recrystallisation fromisopropanol/water.

C₂₀ H₂₄ N₆ O.1.75H₂ O: Found: C, 60.68; H, 6.71; N, 21.12; requires: C,60.66; H, 7.00; N, 21.22%.

EXAMPLE 8

(i) Substituting 2,3-dichloropyridine (5 g) for 2-bromo-5-methylpyridineand using the corresponding molar proportions of the other reagents inthe method of Example 2(i) gave 2-(3-aminopropylamino)-3-chloropyridine(4.86 g) as an oil which was used without further purification.

(ii) Substituting 2-(3-aminopropylamino)-3-chloropyridine (2.2 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(3-chloropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone1.8 H₂ O, (3.6 g; 86%) m.p. 91°-94° C. on recrystallisation fromisopropanol/water.

C₁₉ H₂₁ ClN₆ O.1.8H₂ O: Found: C, 54.8; H, 5.46; N, 20.08; Cl 8.44;requires: C, 54.68; H, 5.80; N, 20.16; Cl 8.51.

EXAMPLE 9

(i) Substituting 2,3,5-tribromopyridine (8.0 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave, afterstripping the final chloroform extract, an oil which was taken back upin ether, washed with dilute sodium hydroxide, dried and stripped togive 2-(3-aminopropylamino)-3,5-dibromopyridine (3.88 g) which was usedwithout further purification.

(ii) Substituting 2-(3-aminopropylamino)-3,5-dibromopyridine (2.0 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(3,5-dibromopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonedihydrate, (2.44 g; 81%) m.p. 160°-62° C. on recrystallisation fromisopropanol/water.

C₁₉ H₂₀ BrN₆ O.2H₂ O: Found: C, 41.85; H, 4.42; N, 15.30; Br, 29.48%;requires: C, 41.93; H, 4.44; N, 15.44; Br, 29.37%.

EXAMPLE 10

(i) Substituting 2-bromo-3,5-dichloropyridine (7.4 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave, on using etherfor the final extraction, 2-(3-aminopropylamino)-3,5-dichloropyridine(4.87 g) as an oil which solidified on standing and was used withoutfurther purification.

(ii) 2-(3-Aminopropylamino)-3,5-dichloropyridine (1.0 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) werefused together on an oil bath at 140° C. for 5 hr. On cooling, water wasadded, the pH adjusted to 7 and the resulting solid filtered off.Chromatography (silica gel, chloroform/methanol, graded elution 50:1 to35:1) and recrystallisation from methanol afforded2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone,(0.55 g; 33%) m.p. 147°-48° C.

C₁₉ H₂₀ Cl₂ N₆ O: Found: C, 54.26; H, 4.59; N, 19.94; Cl, 17.19%;requires: C, 54.42; H, 4.81; N, 20.04; Cl, 16.91%.

EXAMPLE 11

(i) Substituting 2,5-dibromo-3-methylpyridine (5.0 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave, on using etherin the final extraction, 2-(3-aminopropylamino)-5-bromo-3-methylpyridine(1.8 g) as an oil which was used without further purification.

(ii) Substituting 2-(3-aminopropylamino)-5-bromo-3-methylpyridine (1.76g) for 2(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone2.1 H₂ O, (2.44 g; 85%) m.p. 48°-51° C. on recrystallisation fromisopropanol/water.

C₂₀ H₂₃ BrN₆ O.2.1H₂ O: Found: C, 50.17; H, 5.45; N, 17.62; Br, 16.45%;requires: C, 49.92; H, 5.70; N, 17.47; Br, 16.61%.

EXAMPLE 12

(i) Substituting 2-bromo-5-chloro-3-methylpyridine (21 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave on using etherin the final extraction,2-(3-aminopropylamino)-5-chloro-3-methylpyridine (15.5 g) as an oilwhich was used without further purification.

(ii) Substituting 2-(3-aminopropylamino)-5-chloro-3-methylpyridine (10g) for 2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonedihydrate, (15.25 g; 83%) m.p. 140°-43° C. on recrystallisation fromisopropanol/water.

C₂₀ H₂₃ ClN₆ O.2H₂ O: Found: C, 55.34; H, 6.15; N, 19.38; Cl, 8.11%;requires: C, 55.23; H, 6.26; N, 19.32; Cl, 8.15%.

EXAMPLE 13

(i) 2-Chloro-3-methyl-5-nitropyridine (15.5 g), 1,3-diaminopropane (30ml) and pyridine (10 ml) were stirred together and, after the initialexotherm had subsided, the mixture was heated under reflux for 1.5 hr.On cooling the mixture was treated with methanol and the bulk ofcrystalline bi-product filtered off. The solution was stripped, theresidue taken up in water and the pH adjusted to 6.5 with hydrochloricacid. After filtering through `Hyflo` the solution was extracted withchloroform. The pH was raised to 14, (NaOH) and extracted with ether.After drying (K₂ CO₃), the ether extracts were stripped to give a yellowsolid which was triturated with ether/pentane to give2-(3-aminopropylamino)-3-methyl-5-nitropyridine, (12.9 g; 68%) m.p.93°-95° C.

(ii) 2-(3-Aminopropylamino)-3-methyl-5-nitropyridine, (1.58 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.44 g) wereheated together under reflux in pyridine (3 ml) for 22 hr. On cooling,the mixture was treated with ethanol and a mustard coloured solidfiltered off (1.88 g,) m.p. 166°-68° C. Recrystallisation from dimethylformamide/ethanol and finally twice from dimethyl formamide/water gave2-[3-(3-methyl-5-nitropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonehemihydrate (1.67 g; 74%) m.p. 110° C. (softens).

C₂₀ H₂₃ N₇ O₃. 0.5H₂ O: Found: C, 57.67; H, 5.86; N, 23.59; requires: C,57.40; H, 5.78; N, 23.43%.

EXAMPLE 14

(i) 2-Chloro-5-fluoro-3-methylpyridine (5.4 g) 1,3-diaminopropane (15ml) and pyridine (4 ml) were heated together under reflux for 12 hr. Themixture was stripped, the residue taken up in water and the pH adjustedto 6.5 with hydrochloric acid. After extracting with chloroform the pHwas raised to 13 (NaOH) and extracted with ether. After drying (K₂ CO₃)the ether extracts were stripped to give a waxy solid (3.75 g). The H₁-nmr spectrum of this material indicated a mixture of3-(3-aminopropylamino)-6-chloro-5-methylpyridine and2-(3-aminopropylamino)-5-fluoro-3-methylpyridine in the ratio 4:1.

(ii) The above mixture (2.6 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (2.9 g) wereheated together under reflux in pyridine (20 ml) for 24 hr. The mixturewas stripped and the residue chromatographed (silica gel, chloroform,chloroform/methanol graded 50:1 to 20:1). Fractions containing thefaster running component were combined and stripped to give a creamcoloured solid (0.5 g). Recrystallisation twice from methanol andfinally from methanol/water gave2-[3-(5-fluoro-3-methylpyrid-2-yl-amino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone1.75 H₂ O, m.p. 120°-25° C. (softens).

C₂₀ H₂₃ FN₆ O.1.75H₂ O: Found: C, 57.91; H, 6.17; N, 20.06; requires: C,58.03; H, 6.45; N, 20.30%.

Fractions containing the slower running component were combined andstripped to a brown oil. This was taken up in methanol, and aftertreatment with charcoal, water was added to give a solid which onrecrystallisation from ethanol/water afforded2-[3-(6-chloro-5-methylpyrid-3-ylamino)propyl-amino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonehemihydrate (0.47 g) m.p. 110°-15° C. (softens).

C₂₀ H₂₃ ClN₆ O.0.5H₂ O: Found: C, 58.93; H, 5.82; N, 20.61; Cl, 8.58;requires: C, 58.89; H, 5.93; N, 20.60; Cl, 8.69%.

EXAMPLE 15

(i) 2-Bromo-3,5-dimethylpyridine (12.7 g) 1,3-diaminopropane (31 ml) andpyridine (7.5 ml) were heated together under reflux for 12 hr. Workingup the reaction as in the method of Example 14(i) gave2-(3-aminopropylamino)-3,5-dimethylpyridine as an oil (2.45 g) which wasused without further purification.

(ii) 2-(3-Aminopropylamino)-3,5-dimethylpyridine (0.81 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) werefused together on an oil bath at 140° C. for 6 hr. On cooling theresulting mixture was equilibrated between chloroform and water (pHadjusted to 5.5 with dil. hydrochloric acid). The pH of the aqueoussolution was raised to 6.5 and the product extracted out withchloroform. After drying (MgSO₄) and stripping, recrystallisation fromethyl acetate and finally twice from ethanol/water gave2-[3-(3,5-dimethylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone2.4H₂ O, (0.83 g; 49%) m.p. 104°-5° C. (softens ca 90° C.).

C₂₁ H₂₆ ClN₆ O.2.4H₂ O: Found: C, 59.59; H, 7.07; N, 19.96; requires: C,59.81; H, 7.36; N, 19.93%.

EXAMPLE 16

2-(3-Aminopropylamino)pyridine (0.91 g) and5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.33 g) were fusedtogether on a oil bath at 160° C. for 2.5 hr. The mixture was dissolvedin hot ethanol. Cooling afforded a white solid which onrecrystallisation from ethanol gave5-(4-chlorobenzyl)-2-[3-(pyrid-2-ylamino)propylamino]-4-pyrimidone,(1.24 g; 67%) m.p. 168°-71° C.

C₁₉ H₂₀ ClN₅ O: Found: C, 61.41; H, 5.42; N, 18.83; requires: C, 61.70;H, 5.45; N, 18.94%.

EXAMPLE 17

2-(3-Aminopropylamino)-3-chloropyridine (1 g) and5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.3 g) were heatedtogether under reflux in pyridine (20 ml) for 48 hr. The mixture wasstripped and recrystallised from dimethyl formamide/ethanol/water togive5-(4-chlorobenzyl)-2-[3-(3-chloropyrid-2-ylamino)propylamino]-4-pyrimidone0.7H₂ O, (1.55 g; 76%) m.p. 180°-81° C.

C₁₉ H₁₉ ClN₅ O.0.7H₂ O: Found: C, 54.87; H, 5.02; N, 17.01; Cl, 17.09;requires: C, 54.74; H, 4.93; N, 16.80; Cl, 17.01%.

EXAMPLE 18

2-(3-Aminopropylamino)-5-chloro-3-methylpyridine (0.92 g) and2-methylthio-5-(4-pyridylmethyl)-4-pyrimidone (0.90 g) were heatedtogether under reflux in pyridine (5 ml) for 46 hr. After stripping todryness the residue was triturated with wet ether to give a white solid.Repeated recrystallisation from isopropanol/water gave2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(4-pyridylmethyl)-4-pyrimidone(0.95 g; 64%) m.p. 90°-92° C.

C₁₉ H₂₁ ClN₆ O: Found: C, 58.87; H, 5.20; N, 21.58; Cl, 8.84; requires:C, 59.29; H, 5.50; N, 21.84; Cl, 9.21%.

EXAMPLE 19

(i) Substituting 1,4-diaminobutane (440 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 1(i) and heating under reflux for 4 hr gave, afterdistillation, 2-(4-aminobutylamino)pyridine, (131.1 g; 79%) b.p.₀.3128°-30° C.

(ii) Substituting 2-(4-aminobutylamino)pyridine (1.8 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[4-(pyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone,(2.78 g; 76%) m.p. 184° C. on recrystallisation from ethanol.

C₂₀ H₂₄ N₆ O: Found: C, 65.54; H, 6.51; N, 23.21; requires: C, 65.89; H,6.64; N, 23.07%.

EXAMPLE 20

(i) Substituting 1,2-diaminoethane (10.16 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 3(i) gave, on using ether for the final extraction,2-(2-aminoethylamino)-5-chloropyridine (3.57 g) as an oil which was usedwithout further purification.

(ii) Substituting 2-(2-aminoethylamino)-5-chloropyridine (2.0 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[2-(5-chloropyrid-2-ylamino)ethylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonehemihydrate, (2.95 g; 75%) m.p. 164°-66° C. on recrystallisation fromisopropanol/water.

C₁₈ H₁₉ ClN₆ O.0.5H₂ O: Found: C, 57.25; H, 5.31; N, 22.18; Cl, 9.18;requires: C, 56.92; H, 5.31; N, 22.13; Cl, 9.33%.

EXAMPLE 21

(i) Substituting 1,4-diaminobutane (15.8 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 3(i) gave, on using ether in the final extraction,2-(4-aminobutylamino)-5-chloropyridine (6.53 g) as an oil which was usedwithout further purification.

(ii) Substituting 2-(4-aminobutylamino)-5-chloropyridine (2 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(i) gave2-[4-(5-chloropyrid-2-ylamino)butylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone,(2.34 g; 76%) m.p. 214°-15° C. on recrystallisation from dimethylformamide/ethanol.

C₂₀ H₂₃ ClN₆ O: Found: C, 59.81; H, 5.69; N, 20.71; Cl, 8.51; requires:C, 60.2; H, 5.82; N, 21.08; Cl, 8.89.

EXAMPLE 22

(i) Substituting 1,4-diaminobutane (15.8 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 8(i) gave, on using ether for the final extraction2-(4-aminobutylamino)-3-chloropyridine (4.44 g) as an oil which was usedwithout further purification.

(ii) Substituting 2-(4-aminobutylamino)-3-chloropyridine (1.8 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[4-(3-chloropyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(2.35 g; 78%) m.p. 180°-82° C. on recrystallisation from ethanol.

C₂₀ H₂₃ ClN₆ O: Found: C, 60.22; H, 5.70; N, 21.07; Cl, 8.64; requires:C, 60.20; H, 5.82; N, 21.08; Cl, 8.89%.

EXAMPLE 23

(i) Substituting 1,2-diaminoethane (9.0 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 12(i) gave2-(2-aminoethylamino)-5-chloro-3-methylpyridine (3.37 g) as an oil whichwas used without further purification.

(ii) Substituting 2-(2-aminoethylamino)-5-chloro-3-methylpyridine (3.35g) for 2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[2-(5-chloro-3-methylpyrid-2-ylamino)ethylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone1.45H₂ O, (5.28 g; 86%) m.p. 112°-15° C. on recrystallisation fromisopropanol/water.

C₁₉ H₂₁ ClN₆ O.1.45H₂ O: Found: C, 55.81; H, 5.60; N, 20.35; Cl, 8.49;requires: C, 55.53; H, 5.80; N, 20.47; Cl, 8.64%.

EXAMPLE 24

(i) Substituting 1,4-diaminobutane (13.2 g) for 1,3-diaminopropane andusing the corresponding molar proportions of the other reagents in themethod of Example 12(i) gave2-(4-aminobutylamino)-5-chloro-3-methylpyridine (3.8 g) as an oil whichwas used without further purification.

(ii) 2-(4-Aminobutylamino)-5-chloro-3-methylpyridine (1.81 g) and2-nitroamino-5-(6-methylpyrid-3ylmethyl)-4-pyrimidone (1.95 g) werefused together on an oil bath at 140°-50° C. for 2 hr. On cooling themixture was treated with water and dilute hydrochloric acid and somesolid material removed at pH 4. On raising the pH to 5 a precipitate wasobtained which on recrystallising twice from dimethyl formamide/watergave2-[4-(5-chloro-3-methylpyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(1.2 g; 39%) m.p. 202°-3° C.

C₂₁ H₂₅ ClN₆ O: Found: C, 61.18; H, 5.91; N, 20.38; Cl, 8.29; requires:C, 61.08; H, 6.10; N, 20.35; Cl, 8.59%.

EXAMPLE 25

(i) 2-(Aminopropylamino)-5-chloro-3-methylpyridine (3.17 g) and2-nitroamino-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone (3.67 g)were heated together under reflux in pyridine (30 ml) for 7 hr. Themixture was stripped and the residue recrystallised twice fromisopropanol/water to give2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone(3.51 g; 66%) m.p. 128°-31° C.

(ii) Trifluoroacetic anhydride (9 ml) was added to a stirred suspensionof2-[3-(5-chloro-3-methylpyrid-2-ylaminopropylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone(3.45 g) in dry dichloromethane (70 ml) at room temperature. On solutionthe mixture was set aside for 6 days. After this time the mixture wasstripped to dryness and then stripped to dryness twice from methanol.The residue was taken up in water and extracted with chloroform. The pHof the aqueous solution was raised to 4.5 and extracted again withchloroform. The pH was finally adjusted to 6.5 to yield a precipitatewhich was recrystallised from dimethyl formamide/ethanol to give2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidonemonohydrate, (0.58 g; 17%) m.p. 207°-209° C.

C₂₀ H₂₃ ClN₆ O.1H₂ O: Found: C, 57.92; H, 5.85; N, 20.26; Cl, 8.34;requires: C, 57.62; H, 6.04; N, 20.16; Cl, 8.50%.

EXAMPLE 26

(i) 2-(3-Aminopropylamino)-3,5-dichloropyridine (1.43 g) and2-nitroamino-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone(1.52 g)were heated together under reflux in pyridine (15 ml) for 7 hr. Thesolution was stripped and the residue boiled with chloroform. Oncooling, the solid obtained was recrystallised from dimethyl formamideto give2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone,(1.5 g; 63%) m.p. 208°-210° C.

(ii) Substituting2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone(1.45 g) for2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidoneand using corresponding molar proportions of the other reagents in themethod of Example 25(ii) gave, after chromatography (silica gelchloroform/methanol graded 50:1 to 20:1) and repeated recrystallisationfrom dimethyl formamide/ethanol and finally dimethylformamide/ethanol/water2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone,(0.2 g; 14%) m.p. 184°-186° C.

C₁₉ H₂₀ Cl₂ N₆ O₂ +1% NaCl: Found: C, 51.80; H, 4.70; N, 19.06; Cl,16.56; requires: C, 51.90; H, 4.59; N, 19.11; Cl, 16.73%.

EXAMPLE 27

(i) Substituting 2-bromo-4-methylpyridine (25.8 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave2-(3-aminopropylamino)-4-methylpyridine, (16.1 g; 65%) b.p.₀.01-0.02120°-124° C.

(ii) Substituting 2-(3-aminopropylamino)-4-methylpyridine (1.0 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(4-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone0.3 H ₂ O, (1.41 g; 77%) m.p. indeterminate, on the recrystallisationfrom ethanol/water.

C₂₀ H₂₄ N₆ O.0.3H₂ O: Found: C, 64.75; H, 6.67; N, 22.93; requires: C,64.95; H, 6.70; N, 22.72.

EXAMPLE 28

(i) Substituting 2-bromo-6-methylpyridine (25.8 g) for2-bromo-5-methylpyridine and using the corresponding molar proportionsof the other reagents in the method of Example 2(i) gave2-(3-aminopropylamino)-6-methylpyridine, (11.11 g; 45%) b.p.₀.4121°-123° C.

(ii) Substituting 2-(3-aminopropylamino)-6-methylpyridine (1.0 g) for2-(3-aminopropylamino)pyridine and using the corresponding molarproportions of the other reagents in the method of Example 1(ii) gave2-[3-(6-methylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone0.5 H₂ O, (1.21 g; 65%) m.p. ca. 113°-120 ° C. on recrystallisation fromethanol/water.

C₂₀ H₂₄ N₆ O.O.5H₂ O: Found: C, 64.30; H, 6.55; N, 22.75; requires: C,64.32; H, 6.46; N, 22.50%.

What is claimed is:
 1. A compound of the formula: ##STR4## where R² isC₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, nitro, cyano or trifluoromethyl;R³ ishalogen; and a is 2 to
 4. 2. A compound according to claim 1 where R₃ ischlorine.